Herbs-drugs interactions. Outline Evidence for herb-drug interactions Pharmacokinetic (PK) versus pharmacodynamic (PD) interactions St. John ’ s

Herbs-drugs interactions

OutlineEvidence for herb-drug interactionsPharmacokinetic (PK) versus pharmacodynamic (PD) interactionsSt. Johns wortWarfarinMiscellaneousHerb-drug interactions and surgical/dental proceduresUse of computer databases for clinical questions

Learning objectivesDistinguish between pharmacokinetic and pharmacodynamic interactions.Know the principal pharmacokinetic and pharmacodynamic interactions of St Johns Wort, i.e. induction of CYP450 3A4, and serotonin syndrome/photosensitivityKnow the main reasons for herb-drug interactions with warfarin, i.e. vitamin K activity; decreased GI absorption or CYP450 2C9 metabolism; and herbs that decrease platelet aggregation or thromboxane synthesis or have coumarin content. Know the main reasons for caution with herbs and surgery or dental procedures, i.e., herbal anticoagulants (cause bleeding), sedative or stimulant herbs (modify anesthesia).Know principles for clinical coping with herb-drug interactions

Evidence for herb-drug interactionsCase reportsUnderreported? 70% dont ask-dont tellLab studiesDefine mechanismsRecent interest in CYP450 inductionNot necessarily borne out in trials Human studies interpret with cautionTrials using probe drugsMay be too short or expensiveMay be done on healthy population (not always)Genetic polymorphismsMultiple drug/herb users, elderly patientsDe Smet, Br J Clin Pharm 2006; 63:258-67

Drug Interaction ResolutionRequire dosage adjustmentsTemporary or complete elimination of one or the other agent to avoid serious consequencesClose monitoring of the subjectTotal change of drug therapy

PK vs PD reviewPK: absorption, distribution, metabolism, eliminationCYP450, PgPAbsorption from GI tract (laxatives)PD: pharmacological functionAnticoagulant drugs plus anticoagulant herbsSedative herbs plus anesthesiaNegativeMostPositive or synergisticPossible PD or PKDecrease side effects

Prevalence: Canadian seniorsCanadian seniors with osteoarthritisSurvey, n = 191. Average 2.8 prescriptions, 1.9 self-care productsPotential interactions detected using standard databases214 instances, 14% possible clinical significance7 herbs/supplements, associated with 5 clinically insignificant interactions1 recommendation to stop medications (dilatiazem + atrorvastatin -> statin side effects intensified)Clinically significant interactions may be rare but thus easier to forget about and harder to monitor!Putnam, Can Fam Physician 2006; 52:340-45

Prevalence: Mayo Clinic6 specialty areas Survey of 1795 patients; 39.6% used supplementsPotential interactions detected using Lexi-Interact (available on PDA)107 interactions with potential clinical significanceGarlic, valerian, kava, ginkgo and St. Johns wort accounted for most potential interactions 68%Antithrombotics, sedatives, antidepressants, and antidiabetics most involved in interactions 94%No patient was seriously harmed by herb-drug interactionSood et al. 2008; 121(3):207-11

St. Johns wort (Hypericum perforatum)Mild-moderate depression; multiple clinical trials, fewer AEs than conventional drugsCase reports suggesting PK interactions (most important of SWJ interactions)Lab and clinical studies indicate PK interactions:CYP450 3A4 mechanism short-term inhibitionLong-term induction; of most importance clinicallyReduces various drugs to subtherapeutic levelsHyperforin, an active constituent, is a ligand for the xenobiotic pregnane X receptor -> CYP450 3A4

St Johns wortOther PK interactionsP-glycoprotein (PgP): involved in multidrug resistance, acts as a pump to remove drugs from cellsSJW induces; thus removes drugs from cellsAlso regulates MDR-1 (multidrug resistance gene) and other drug transportersChavez, Life Sci 2006; 78:2146-57

St. Johns wort: PK interactionsHuman trial with irinotecan (cancer)Blood levels of active metabolite were reducedOther drugs affectedCyclosporin, tacrolimus, indinavir, nevirapine, imatinib, alprazolam, midazolam, amitriptyline, digoxin, fexofenadine, methadone, omeprazole, theophylline, verapamil, etoposide. Human study with oral contraceptives indicating reduced OC exposure and breakthrough bleeding (pregnancies resulted). Case of delayed emergence from general anesthesia observed. Multiple potential interactions with oncology drugs (but rare use by oncology patients?).Other CYP450sMay inhibit CYP1A2, does not inhibit CYP2D6, hyperforin inhibits CYP2C9Murphy Contraception 2005; 71:402-8

St. Johns wortPD interactionsWith other antidepressantsSerotonin syndromeSJW has both SSRI and MAO inhibitor activityRestlessness, nausea, vomiting, tachycardia, hallucinations etc.Case reports with buspirone, loperamil, nefazodone, paroxetine, sertraline, venlafaxinePossible adrenergic crisisMAO inhibitor activity (not major activity)

Clinical strategyAvoid use with other medications unless checked out in an interaction database. Will have similar interaction profile to other CYP450 3A4 inducers.Major drug-drug interaction pathway

Warfarin-herb interactionsNumerous drug-drug interactions: macrolides, NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc (variable quality of evidence).Possible pathways: Vitamin K activity lowers INRFoods: leafy greens (healthy diet)Green drinks clinical interactions with oncology patients. Case reports with cranberry juice also.Multivitamins (low vitamin K dose)CoQ10: similar structure to vitamin K, but RCT found no effect on INR. Case reports suggest monitoring.

Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5Engelsen, Throm Hemost 2002; 87:1075-6

Warfarin-herb interactionsPK decreased absorption from GI tract due to mucilage (comfrey, Iceland moss) or laxative herbs (senna, rhubarb etc)CYP450 2C9 inhibition/induction, which metabolizes the active S-enantiomer of warfarin (saw palmetto, kava, bromelain possible but only lab data)PD Herbs that decrease platelet aggregationDecreased thromboxane synthesisHerbs with coumarin content (though coumarin is a relatively weak anticoagulant)

Warfarin and Chinese herbsAsian ginseng (Panax ginseng) ginsenosides may inhibit platelet aggregation (anticoagulant). RCTs in in healthy volunteers & cardiac patients showed no effect of Asian ginseng on INR, platelet aggregation. Monitor closely.American ginseng (Panax quinquefolius) RCT in healthy volunteers indicated moderately reduced INR, warfarin levels, AUC. Avoid with warfarin.Many other Asian herbs with known platelet aggregation inhibition but no clinical study.Chavez, Life Sci 2006; 78:2146-57Jiang, Br J Clin Pharm 2004; 57:592-9Yuan, Ann Intern Med 2004; 141:23-7Lee, Int J Cardiol 2010; 145: 275-6

Warfarin and G herbsGarlic (Allium sativum) 2 case reports. Continuing ingestion of high levels of garlic or garlic oil can decrease platelet aggregationGinger (Zingiber officinalis) Inconclusive results in studies in healthy volunteers but case reports exist. Ginkgo (Ginkgo biloba) Ginkgolide B decreases PAF, extract inhibits thromboxane and prostacyclin in diabetics. Preliminary human study indicates no effect on INR, but a case report suggests interaction Green tea (Camellia sinensis) Inhibits platelet synthesis of thromboxane (lab). Case report of decreased INR in patient drinking 1 gal/day green tea vitamin K.Chavez, Life Sci 2006; 78:2146-57

Warfarin and lipid-based agentsOmega-3 fatty acids (fish oil, algal formulas) case report of increased INR with fish oil in a stabilized warfarin patient, 67-y/o female.Strong antiinflammatory effects, but did not affect INR in an RCT.Saw palmetto lipid extract. Case report of intraoperative hemorrhage (w/o warfarin) and increased INR in 2 warfarin patients.Chavez, Life Sci 2006; 78:2146-57

Garlic (Allium sativum)Drug Interactions:Alters pharmacokinetic variables of acetaminophenClinical trial: Inhibits CYP2E1No effect on warfarin PK or PD in 2 clinical trials but 2 cases reported in one paper, INRProduced hypoglycemia with chlorpropamide case but bitter melon, another herbal hypoglycemic, also in curry that caused effect

Izzo AA, Ernst E. Drugs, 2001, 61:2163-2175

Garlic (Allium sativum)Drug Interactions:Saquinavir (Fortovase) study-10 healthy volunteersAUC during the 8 hour dosing interval decreased by 51% 10 day wash out needed before Cmax, AUC levels returned to 60-70% of normalRitonavir possible interaction with garlic PK or PD, resulting in garlic toxicity to GI tractGarlic and Protease Inhibitors should be avoided

Clin Infect Dis, 2002, 34:234-238.

Herbs and diabetesNumerous herbs used for diabetes have shown laboratory effects on hypoglycemia; case reports suggesting interaction beginning to appear in literature.Examples: bitter melon, nopal or prickly pear cactus, gymnema, fenugreek, ginseng (Asian, American), cinnamon, glucomannan, guar gum, chia and others. Need to be discussed with patients.

Herbs and StatinsPharmacodynamic interactions: the herbal statins (frequently in cholesterol-lowering supplements). Effect on statin side effects (liver, myalgia, rhabomyolysis)? Usually due to polypharmacy.

Red yeast rice (monacolin = lovastatin); case report of rhabdomyolysis with lovastatin and cyclosporine after initiating red yeast rice pantethine (a stabilized form of vit B5 included in some cholesterol lowering supplments) artichoke reishi mushroomtocotrienols policosanol guggul garlic fish oil (also raises LDL cholesterol)possibly goldensealresveratrolplant stanolschlorogenic acid (coffee, though not absorbed easily) luteolin (parsley, peppers) luteolin 7-0-glucoside (dandelion flower) Armitage 2007; Lancet 370; 1781-90; NAPRALERT; naturalstandard.org

Herbs and StatinsPharmacokinetic interactions:CYP450 3A4: lovatstatin, simvastatin, atrorvastatin. CYP 2C9: fluvastatin, rouvastatin, pitavastatinHerb/supplement 3A4 and 2C9 inhibitors/inducers:berberineOregon grape (contains berberine)bromelainresveratrolcranberrySt. Johns wortDHEAschizandrauncariafeverfewAlso grapefruit juice

GinkgoCases/trials on interactions:Aspirin hyphemaAcetaminophen - bilateral subdural hematomasWarfarin - intracerebral hemorrhage but no effect in 2 clinical trialsIbuprofen -- cerebral hemorrhageRofecoxib bleeding, case reportValproate: 2 cases of seizuresRisperidone priapism; vasodilating effect of both substances?Induction of CYP2C19 clinical trial, case report. Possible/weak effects on CYPs 3A4 and 2C9

Ginkgo and psychotropicsFemale with Alzheimer disease was switched from bromazepam and vitamin E to trazodone and ginkgo. Lapsed into a coma, but was reversed by giving flumazenil. Ginkgo increases GABA, causing coma, by binding to benzodiazepine receptor and inducing activation of trazodone through CYP3A4. Flumazenil antagonizes benzodiazepine receptor, decreasing GABA enough to break the coma.Antioxidant effect may result in enhanced activity of haloperidol.Galluzzi, J Neurol Neurosurg Psych 68:679-80Zhang, J Clin Psychopharm 21:85-88

Kava (Piper methysticum)One case report of coma induced by a combination of kava and alprazolam-a benzodiazepine Extrapyramidal side effects-4 cases of dopamine antagonism-oral, lingual and trunk dyskinesiaInhibition of CYP2E1 clinical trialDo not combine with alcohol, sedatives, tranquilizers or CYP2E1 substrates

Licorice (Glycyrrhiza glabra)Sore throat, dyspepsia, peptic ulcer diseaseTriterpene saponins-glycyrrhizinProlonged use > 6weeks of >50 g/day-pseudaldosteronismPotassium depletion, sodium retention, edema, hypertension and weight gainDrug InteractionsThiazide and loop diuretics, cardiac glycosidesAntihypertensivesSpironolactone or amilorideVerapamil (animal study)Only clinically significant in cases of excessive use, however appears with excessive licorice candyPossible with multiple use of herbal formulas containing licorice (ie in Chinese formulas)

Licorice: positive interactionSmall trial of women being treated for polycystic ovary syndrome with spironolactone, which has side effects of diuresis, low blood pressure, volume depletion. 20% of drug-alone, none of drug + licorice had symptoms, also metrorrhagia improved. Also useful due to estrogenic effect of licorice.

Armanini Eur J Obst Gynecol Reprod Biol. 2007; 131:61-7

Herbal laxativesDecrease blood levels of drugs by shortening gastrointestinal transit timeIncrease potassium lossCommon herbal laxatives: aloe, cascara sagrada, rhubarb, senna

Abebe W, 2003. J Dental Hygiene 77(1):37-46

Other potential interactionsEphedra (diet pills) illegal in US but possibly obtained internationally/Internet. Increase in blood pressure, thus contraindicated with antihypertensives and stimulants (e.g. caffeine).Black Cohosh (menopausal symptoms but UIC trial negative) some hepatotoxicity due to adulteration recently; use cautiously.Ginkgo 2 case reports of interaction with phenelzine; insomnia, headache, irritabilityHawthorn interference with digoxin blood level tests; possible pharmacodynamic interaction

Other possible interactionsTamoxifen inhibitors of CYP2D6 should not be taken because of metabolism of prodrug to its active form. Genetic polymorphism in population. Several antidepressants are strong inhibitors but SJW is weak if at all. Valerian in vitro activity. Goldenseal strong inhibition in clinical trial.Chinese herbs Scutellaria species induction of CYP2E1, 2C9. Angelica dahurica inhibited CYP1A2 (but no effect of Angelica tenuissima). Hundreds of other Asian herbs with no info.

Surgery and Dental ProceduresDrug interactions and physiological reactions:CNS herbs: potential PD interactions with anesthesia:Valerian, kava, St. Johns wort (PK interaction also), lavender, passionflower, lemon balm, ashwaganda, ginseng, ephedra). Midazolam SJW, goldenseal and possibly ginkgo PK effects but ginkgo studies are contradictoryBlood sugar ginseng, bitter melon, chromium, fenugreek, cinnamonAng-Lee, JAMA 2001; 286:208-16

Surgery and Dental ProceduresAnticoagulant herbs: post-op bleeding and interaction with aspirin or other NSAIDs that may cause bleeding.Garlic, ginger, ginkgo, ginseng, feverfew.Angelica, asafoetida, anise, astragalus, arnica, bogbean, bromelain, borage seed, capsicum, clove, curcumin, dong quai, fenugreek, fish oil, green tea, horsechestnut, juniper, licorice, meadowsweet, onion, pau darco, parsley, passionflower, quassia, red clover, reishi, salvia, turmeric, willow.

Surgery and Dental ProceduresStop herb and supplement use 7-14 days prior to surgery.All pre-surgical patients should be questioned about herb/supplement use to determine recent consumption of anticoagulant or drug-interacting herbs.

Dental procedures: herb side effectsFeverfew (Tanacetum parthenium): mouth sores and irritation if leaves are chewedFeverfew, ginkgo: gingival bleeding due to anticoagulant effectEchinacea (Echinacea purpurea) and kava (Piper methysticum): tongue numbnessSt Johns wort: xerostomiaYohimbine (Pausinystalia yohimbe): salivation

Clinical copingCounteract dont ask-dont tellOpen and nonjudgmental discussionFollow up herb use found in case historiesExplain importance of potential interactionsAvoid SJW and warfarin interactionsPatients on complicated medical regimens should avoid herbs and supplements unless carefully screened/supervised, but prioritize drugs with narrow therapeutic index, ie: carbamazepine, cyclosporine, digoxin, ethosuximide, levothyroxine, phenytoin, procainamide, theophylline and warfarin

Checking for herb-drug interactionsNatural Standard (www.naturalstandard.com). Subscription service.Partial database at MedlinePlus.govNatural Medicines Comprehensive Database (www.naturaldatabase.com). Subscription service.Lexi-Interact. Subscription service (www.lexi-comp.com)MicroMedex Altmedex. Subscription service (www.micromedex.com) Some misleading information but generally err on the side of pointing out interactions for which there is little to no evidence base.

The issue50% of people who reported that they used complementary and alternative therapies also used conventional medicines on the same day

57% did not report the use of complementary therapies to their doctor. MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.

Steps for Detecting and Advising on Herbal/Drug InteractionsIs the patient taking any herbal supplements?

Does the herbal have efficacy for the intended use?

Is the product reliable? (i.e.,what are they REALLY taking?)

Is the Rx drug one with a narrow therapeutic margin?

Evaluation of Herbal/Drug InteractionsSpeculative or Theoreticale.g. St. Johns Wort and tyramine containing foods due to MAOI effects or evening primrose oil and risk for bleeds with warfarinIn vitro effectse.g. ginkgo and microsomal studies showing inhibition of CYP2C9In vivo - animal studiese.g. kava and alcoholIn vivo - human case reportse.g. ginkgo and warfarin bleedsIn vivo - healthy human volunteer studiese.g. indinivir and St. Johns WortIn vivo - clinical studies in patients

Important Criteria for Evaluation of a Human Herbal/Drug Interaction ReportReputable standardized product used and carefully described?Product used analyzed for marker compounds?Same batch used throughout study?Doses appropriate?Steady state study to discern CYP induction?Is observation consistent with known mechanisms of action?Is observation consistent with literature observations?Randomized, placebo controlled human volunteer study with appropriate n?

Relative Levels of P450 isozymes in human liver

Top 20 Selling Herbals for 2007- Mass Market HerbalGram 2008;78:61-62ProductM $ % change rank in 20061. soy25-1712. cranberry 24+2433. garlic 20-1324. ginkgo 18+125 5. saw palmetto17 - 646. echinacea 16- 967. black cohosh 09-0.588. milk thistle09-0.479. ginseng 08+ 31010. St. Johns wort08- 6911. Green tea 05- 71112. Evening primrose oil04- 91213. valerian03- 91314. Horny goat weed02- 214Red indicates risk for drug interactions

Top 20 Selling Herbals for 2007- Mass Market HerbalGram 2008;78:61-62ProductM $ % change rank in 200415. bilberry02- 91516. grape seed02- 91617. Yohimbe01-151718. red clover01-1318 19. Horse chestnut seed01-211920. ginger0.7-2020

Total (all herbs)268+7.6Red indicates potential risk for drug interactionsNote: total herbal sales are estimated at $4.7 billionThe above figures include only sales from food stores, drug stores, and mass market retailers but with Wal-Mart figures not included. It does not include warehouse buying clubs (Costco), convenience stores, natural foods stores, multilevel marketers, health professional sales, mail order or internet sales.

Herb-drug interactions: potentially important but woefully under researchedE. ErnstEur J Clin Pharmacol 2000: 56: 523-524Why have only so few cases of suspected herb-drug interactions been reported in the medical literature?Truly rare events?Significant unreporting?

Clinical risk management of herb-drug interactionsRisk identification and assessment

Development and implementation of risk reduction strategies

Evaluation of risk reduction strategies

De Smet, PAGM. Br J Clin Pharmacol 2006

Clinical significance of herb-drug InteractionsPatient characteristicsNature of pharmacodynamic responseMechanism of interactionSafety margin of the interacting herb and drugQuality of the productSize of the doseDuration of therapyTime course of drug interactionOrder and timing of administration

PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25

Understanding the mechanism of a herb-drug interaction allows theprediction of other interactionsassessment of clinical significanceguide risk minimisation strategies

Study designs used to assess herb-drug interactionsControlled trials in patientsControlled trials in healthy subjectsCase reports or seriesAnimal studiesIn vitro studiesAdverse event dataTheoretical

PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25

Investigating drug interactionsType of studyEnzyme, Cells or microsomesAnimalsHealthysubjectsPatientsMechanismCostClinical RelevanceEthical Issues

The need to establish qualityCONSORT guidelines for reportingGagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions: An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.

The need to establish quality of herbal medicine productHerbal medicine product nameCharacteristics of herbal product (including part of plant used)Dose and qualitative descriptionQuantitative analysis of HMP (including procedures and standardisation)

Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions: An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.

Stevinson et al. Ann Int Med 133:420-429, 2000

Spontaneous spinal hemoatoma associated with garlicRose et al. Neurosurgery 1990;26:880-882.87 year old male2g of garlic per day for yearspresented with weakness and partial paralysisbleeding time of 11.5 min (normal = 3 min)day 3 post surgery bleed time of 5 min (after stopping garlic)

Other reports: Garlic and TURP bleeding (German et al. Br J Urology 1995;76:518).Garlic and surgery bleeding (Burnham BE; Plastic Reconstr Surgery 1995;95:213).

Piscitelli et al. Garlic and Saquinavir. Clin Infect Dis 2002;34:234-238. N=10 Garlic=GarliPure (Natrol)(BID)

Piscitelli et al. Garlic and Saquinavir. Clin Infect Dis 2002;34:234-238. N=9 Garlic=GarliPure (Natrol)(BID)

Gurley et al. Clin Pharmacol Ther 2002;72:276-287 n=12; note: used garlic oil prep (500mg TID)

Markowitz et al. Clin Pharmacol Ther 2003;74:170, n=14, 3X600mg for 14d (Kwai)

Garlic and warfarinAnother study showed no effect of aged garlic extract (Kyolic) on patients taking warfarin. HDL went up. No other changesMecan et al. J. Nutr. 2006;136:793s-795s.

Garlic summaryEfficacy: ? benefit for use in hyperlipidemia. Possible other cardiovascular benefits.Safety: goodDrug interactions: warfarin; possibly aspirin and other antiplatelet adhesion drugs (pharmacodynamic interaction); not with HIV drugs (other 3A4 substrates?) but depends on product (pharmacokinetic interaction) (maybe raw garlic induces 3A4 but not extracts??)Product selection: Suggest enteric coated tablets standardized to about 4mg allicin yield/tabletDose: equivalent of about 4g (2-3 cloves) of fresh garlic per day i.e. 8-12 mg allicin/d

Gurley et al. Clin Pharmacol Ther 2004;76:428-440.CYP 1A2

Gurley et al. Clin Pharmacol Ther 2004;76:428-440.800mg BID for 30d (Wild Oats Market)(analyzed)CYP 3A4

Gorski et al. Clin Pharmacol Ther 2004;75:89-100N=12 crossover, before and after 400mg QID Echinacea purpurea root extract for 8dA= Cl caffeine (CYP 1A2)

B= Cl tolbutamide (CYP 2C9)

Gorski et al. Clin Pharmacol Ther 2004;75:89-100N=12 crossover, before and after 400mg QID Echinacea purpurea root extract for 8dOpen circle is echinaceaA= midazolam IV (CYP 3A4)

B= midazolam PO (CYP 3A4)

EchinaceaSummaryEfficacy: evidence for treatment not preventionSafety: good; rare allergyDrug interactions: Pharmacodynamic: dont give to patients taking immunosuppressive drugsPharmacokinetic: may inhibit 1A2; may inhibit intestinal 3A4 but induce hepatic so clinical significance unclear; effect on 2C9 is considered minorProduct selection: want standardized extract containing about 4% phenolics. (GWE recommends Echinamide in 2008)Dose: about 250mg QID for treatment Questions remainingWhich product? Tincture? Tablets? Root extract? Flowering tops? Pressed juice? E. purpurea? E. augusifolia? E. pallida?

Bleeds associated with ginkgo use

Patient age

Ginkgo use

Other therapy

Bleed

ref

70

1 week

Aspirin

Iris

1

78

2 mos

Warfarin

Intracerebral

2

33

2 years

None

Subdural

3

61

6 mos

None

Subarachnoid

4

1. NEJM 336:1108,1997

2. Neurology 50:1933-1934,1998

3. Lancet 352:36-37,1998

4. Neurology 46:1775-1776,1996

Ginkgo-warfarin interactions?

IsoformType of InhibitionKi (g/ml)CYP1A2Mixed11.20.6Competitive2.1---

CYP2A6Mixed21.22.1

CYP2C9Competitive9.1---

CYP2D6Competitive133.1---

CYP3A4Mixed17.02.5Non-linear Regression Ki ValuesMohutsky et al. Am J Ther 2006;13:24-31

Tolbutamide Human Study (CYP 2C9 probe)-6 Subjects (3 males, 3 females)-Subjects ingested 500mg tolbutamide and collected 6-12 hour urine (Control phase)-Followed by a 2 week wash-out period-Subjects then ingested two 60mg Ginkgo biloba extract tablets 2 times a day for 3 days-The morning of day 4 patients received a 500mg dose of tolbutamide along with the ginkgo and collected 6-12 hour total urine (Ginkgo phase)Tolbutamide dose2 week wash-out periodGinkgo biloba doseTolbutamide doseMohutsky et al. Am J Ther 2006;13:24-31

Control680 323 Ginkgo610 327Mohutsky et al. Am J Ther 2006;13:24-31

Chart1

921.81111.4185.6572.6736.5551.9

577.91185.5189.9562.3681.9460.2

Metabolic Ratio (4-methylhydroxytolbutamide + carboxytolbutamide / tolbutamide)

Comparison of Tolbutamide Metabolic Ratios

Sheet1

ControlGinkgo

921.8577.9

1111.41185.5

185.6189.9

572.6562.3

736.5681.9

551.9460.2

Sheet2

Sheet3

Diclofenac-Ginkgo Interaction (CYP 2C9 probe)12 healthy non-smoking subjects were recruited (8 males 4 females)50 mg diclofenac potassium (immediate release) was administered every 12 hours for 14 daysOn day 8, 120 mg of Ginkgo biloba extract was added to the diclofenac regimen.On days 7 and 14 plasma collected at times (0, 0.5, 1,2,4,6,8,10, and 12 hrs)12 hour urine collectedDiclofenac 50 mg every 12 hoursGinkgo biloba 120 mg every 12 hoursDay 7 blood drawDay 14 Blood drawMohutsky et al. Am J Ther 2006;13:24-31

Control0.64 0.36Ginkgo0.61 0.33Mohutsky et al. Am J Ther 2006;13:24-31

Chart2

1389.38331234522811.43824062563794.83350207491945.35087057031516.8657738471618.04517612612190.65218684692118.67010108511444.50706710763177.03480451021176.91609412262211.0490334598

1579.40598935852603.89854362893249.63615727622411.7860442408694.99316048221559.46728974652672.67792505641924.66476431091805.32658933541437.57584870841653.59894198672360.5105631636

AUC Diclofenac

Comparison of AUCs

Chart1

27.787666246956.228764812575.896670041538.907017411430.337315476932.360903522543.813043736942.373402021728.890141342263.540696090223.538321882544.2209806692

31.588119787252.077970872664.992723145548.235720884813.899863209631.189345794953.453558501138.493295286236.106531786728.751516974233.071978839747.2102112633

Cl/F (L/hr)

Comparison of Cl/F

Chart3

0.33962703191.03086068821.45193629640.74430815920.30337315480.43147871360.58417391650.44391183070.38520188460.87368457120.26556055460.8107179789

0.38607701960.95476279931.24333905150.92277031260.13899863210.41585794390.71271411330.40326309350.48142042380.39533335840.37311976130.8655205398

Cl/F (L/hr/kg)

Comparison of Diclofenac Clearances from Plasma

Sheet1

AUCCl/F

ControlGinkgoControlGinkgo

meanStandard deviationmeanStandard deviationweights (kg)meanStandard deviationmeanStandard deviation

ControlGinkgoControlGinkgo

subject 11389.41.61579.427.181.8181818182subject 127.80.031.60.5

subject 22811.4186.62603.969.554.5454545455subject 256.23.752.11.4

subject 33794.8134.83249.640.652.2727272727subject 375.92.765.00.8

subject 41945.459.32411.83.352.2727272727subject 438.91.248.20.1

subject 51516.929.0695.030.3100subject 530.30.613.90.6

subject 61618.024.91559.550.275subject 632.40.531.21.0

subject 72190.71.12672.7108.075subject 743.80.053.52.2

subject 82118.724.51924.751.495.4545454545subject 842.40.538.51.0

subject 91444.512.11805.349.875subject 928.90.236.11.0

subject 103177.029.71437.6147.072.7272727273subject 1063.50.628.82.9

subject 111176.964.01653.658.688.6363636364subject 1123.51.333.11.2

subject 122211.034.82360.52.454.5454545455subject 1244.20.747.20.0

2116.22884689341996.128484774542.339.9

794.2589458832689.666211196915.913.8

0.54065178650.54

ControlGinkgo

0.33962703190.3860770196

1.03086068820.9547627993

1.45193629641.2433390515

0.74430815920.9227703126

0.30337315480.1389986321

0.43147871360.4158579439

0.58417391650.7127141133

0.44391183070.4032630935

0.38520188460.4814204238

0.87368457120.3953333584

0.26556055460.3731197613

0.81071797890.8655205398

0.63873623170.6077647541

0.35679680240.3253987467

0.5703018098

Sheet2

Sheet3

Ginkgo biloba - Diclofenac Tolbutamide Human Studies ConclusionsNo difference was observed in the metabolic ratio between the two arms of the study (tolbutamide alone and tolbutamide + Ginkgo)No difference was seen between the clearances of the two arms of the study ( diclofenac alone and diclofenac + Ginkgo)Ginkgo extract does not appear to interact with CYP2C9 substrates in humans

Jiang et al. Br J Clin Pharmacol 2005;59:425-432.N=12 ginkgo for 7d; warfarin alone or in combination with ginkgo or ginger

Engelsen et al, Thromb Haemost 2002;87:1075-6. N=21, double blind, crossover. Rx=1 month with 2 week washout. Dose of warfarin did not change.

Chart1

2.70.34

2.70.38

2.70.36

INR

CoQ10 and Ginkgo on Warfarin

Sheet1

CoQ102.70.34

Ginkgo2.70.38

Placebo2.70.36

Ginkgo and coagulation and pharmacodynamic interactions with antiplatelet adhesion inhibitors

Coagulation in healthy adults (in absence of other drugs) Kohler et al. Blood Coagul Fibrinolysis. 2004;15:303-9. (company study). No effect on coagulation parameters in healthy adults after 7d of EGb761 120mg/d. n=50.

Gardner et al. Blood Coagul Fibrinolysis 2007;18:287-293Aspirin 325mg/d for two weeks prior to 4 weeks Ginkgold 300mg/d

Bleed times; single dose n=80 cilostazol=Pletel clopidrogrel= Plavix

Ginkgo: Potential Interactionswith other drugs (not involving blood coagulation)CYP3A4Markowitz et al. J Clin Psycopharmacol 2003;23:576-581. No effect of multiple dosing of ginkgo on dextromethorphan (2D6) or alprozolam (3A4) pharmacokinetics. n=12Study by Gurley and study by Ushida (see slides)Pgp (p-glycoprotein)Mauro et al. Am J Ther 2003;10:247-251. No effect of multiple dosing of ginkgo on digoxin (Pgp) pharmacokinetics. N=8 crossover2C19Yin et al. Pharmacogenetics 2004;14:841-850. Small induction of 2C19 mediated hydroxylation of omeprazole. 140mg BID x 12d

Gurley et al. Clin Pharmacol Ther 2002;72:276-287 n=12 (CYP 3A4) ginkgo-Wild Oats Markets (24% flavone glycosides, 6% ginkgolides)(analyzed)

Ushida et al. J Clin Pharmcol 2006;46:1290-8 n=12 CYP 3A4 probe is midazolam; note: use Ginkgold 120mg TID!

Ginkgo biloba summaryEfficacy: good for dementia and poor peripheral circulatory problemsSafety: good; rare bleeding episodesDrug interactions: no effect on 3A4,2C9 or 2D6 but may induce 2C19; may inhibit platelet adhesion; possible (not necessarily probable!) interaction with blood thinners and warfarin so avoid or close monitoring needed.Product selection: look for EGb761 extract Dose: 1-2 60mg tabs, BIDQuestions remaining includeExtent of memory improvement in younger patients?Delay Alzheimers and dementia?Help in other circulatory disorders?Synergistic with other drugs and treatments?

Soy and Menopausal and Postmenopausal problemsHot flashes- maybe helpsOsteoporosis-some evidence for helpSoy Effects on CancersLong consumption of soy associated with lower rates of breast, endometrial and prostate cancers (Asian cultures)Soy and some soy isoflavones have unknown effects on estrogen receptor positive breast cancer but may stimulate growthSoy may slightly inhibit prostate cancer growthSoy-Cardiovascular Benefits Favorable effects on cholesterol balance; heart healthyIsoflavones inhibit CYP3A4 in vitro

6-hydroxycortisol/cortisol ratio (CYP 3A4)From: Anderson et al., Clin Pharm and Ther 2003;43:643-648

herbalBaselineWeek 1 TreatmentWeek 2 TreatmentWeek 3 WashoutWeek 4 Statistics

Ginseng 4.4 2.4 3.7 2.2 3.6 1.8 3.7 1.6 NSSoy isoflavones4.9 2.5 5.0 2.0 4.6 2.2 ------- NS

SoyEfficacy: increased soy ingestion may decrease hot flashes and other postmenopausal symptoms; cardiovascular benefits as well. Safety: good but use in breast cancer may be riskyDrug interactions: not with with tamoxifen but effect on CYP3A4 is unlikelyProduct selection: soy or isoflavonesDose: about 20-40g of soy protein has been used. This contains 30-50mg of isoflavones.Questions remaining includeHow much benefit? Safety in breast cancer?

Probable Interaction Between Warfarin and GinsengJanetzky and Morreale, Am J. Health-Syst Pharmacy 54:692-693,1997 47 yr old male on warfarin for 10 years with an INR of 3-4 started ginseng (INR= 3.1, 4 weeks prev) INR declined to 1.5 after 3 weeks on ginsengINR increased to 3.3 after stoppingginseng causing CYP induction?

Yuan, C.-S. et. al. Ann Intern Med 2004;141:23-27Changes in individual peak international normalized ratio (INR), INR area under the curve (AUC), peak plasma warfarin level, and warfarin AUC in weeks 1 and 4 in American ginseng or placebo groups5mg warfarin for 3d before and after 1g/d ginseng (50mg/d ginsenosides) American ginseng (Panax quinquifolius) n=20

Jiang et al. Br J Clin Pharmacol 2004;57:592-599. SJW, ginseng and placebo in triple crossover study. N=12 single dose 25mg warfarin following 7d (ginseng) or 14d (sjw) of herbal; ginseng dose=54mg/d ginsenosides; Korean ginseng (Panax ginseng)

6-hydroxycortisol/cortisol ratio (CYP 3A4)From: Anderson and Elmer, Clinical Pharmacology and Therapeutics 43:643-648 (2003).

herbalBaselineWeek 1 TreatmentWeek 2 TreatmentWeek 3 WashoutWeek 4 Statistics

Ginseng 4.4 2.4 3.7 2.2 3.6 1.8 3.7 1.6 NSSoy isoflavones4.9 2.5 5.0 2.0 4.6 2.2 ------- NS

Gurley et al. Clin Phamcol Ther 2002;72:276-287 n=12; Panax ginseng

GinsengEfficacy: some evidence for applications in geriatric patients (improved quality of life) and in diabetes Safety: good; Drug interactions: no apparent induction of CYP 3A4 but induction of 2C9 (warfarin) with Am ginseng (Panax quinquifolius) but maybe not Panax ginseng. May precipitate hypoglycemia with insulin or oral hypoglycermics. Product selection: product should be standardized so dose is 4-7% ginsenosides/dQuestions remaining include:What, actually is this stuff good for!

Lecrubier et al. Am J Psychiatry 2002;159:1361 n=375

Interactions with St. Johns Wort-cyclosporin-Study: 2 case reports

case 1: 61yr had transplant 11mos earlier; cyclosporin, azathioprine, steroids for 11 mos. Unexplained heart failure noted after SJW started.

case 2: 63yr had transplant 20mos earlier: same senario as case 1. Ref: Ruschitzka et al. Lancet 355:548-549,2000

Markowitz et al. JAMA 290:1500,2003 n=12 14d of SJWCYP 3A4

Durr et al. Clin Pharmacol Ther 2000;68:598-604.

Summary of SJW Interactions (adapted from Henderson et al. Br J Clin Pharmacol 2002;54:349-346)

Drug

CYP

Effect

Management

HIV protease inhibitors

(nelfinavir,ritonavor,saquinavir)

Induce 3A4

(

Stop and measure

viral load

HIV non-nucleoside RTI

(efavirenz,nevirapine)

Induce 3A4

(

Stop and measure

viral load

warfarin

Induce 2C9

(

Stop and adjust warfarin dose

cyclosporin

Induce P-glycoprotein

(

Stop and adjust cyclosporine dose

oral contraceptives

Induce 3A4

(

Stop and use alternate birth control

anticonvulsants

Induce 3A4

(

Stop and adjust anticonvulsant dose

digoxin

Induce P-glycoprotein

(

Stop and adjust digoxin dose

theophylline

Induce 1A2

(

Stop and adjust theophylline dose

Triptans

(sumatriptan)

Increase serotonin

(

Stop

SSRI

(fluoxetine,sertraline, etc)

Increase serotonin

(

Stop

St. Johns WortSummaryEfficacy: good evidence for mild to moderate depressionSafety: dont combine with other medications unless under close monitoring; possible photosensitivityDrug interactions: a problem! Is a broad spectrum P450 inducer and a p-glycoprotein inducer. Product selection: want standardized extract containing about 0.3% hypericin or 1-2% hyperforinDose: about 300mg TID for treatmentQuestions remaining includeHow best to use this herbal given that there are drug interaction problems

Gurley et al. Clin Pharmacol Ther 2005;77:415-426. N=12Potential Interactions of Goldenseal with CYP2D6 and CYP 3A4 substrates

Herbals affecting clottingadapted from Natural Medicine Comprehensive Database and Norred and Brinker, Alt Ther Health Med 2001;7:58-67.Andrographis panuculaBogbeanDevil clawginsengPau darcoangelicaBoldoDong quaigreen teameadow sweetanisecapsicumErigeronhawthornprickly asharnicaceleryEvening primrose oilhorse chestnut barkpassionflowerAsafoetachamomilefeverfewHuang qipopularBaikal skullcapclove oilfish oilhorseradishquassiaBilberrycoleus rootfenugreekkavared cloverBlack current seeddanshengarliclicoricereishi mushroomBladderwrackdandelion rootgingeronionSha shenBomelainDanshenginkgopapainShinpi bark

Sweet birch oilTonka bean turmericvitamin Ewintergreen oilwild carrotwild lettucewillowwood ear mushroomwoodruff

Herbs with clotting problems reported in humans

Ginkgo and garlic and St. Johns wort- see earlier notesEvening primrose oil - human study showed 40% increase in bleed time but no other reportsBorage seed oil - same as evening primrose oilVitamin E - doses >1200 i.u./d can increase bleed timeCranberry juice case reports of increased INR (salicylic acid? CYP 2C9 inhibition?) but in vivo study showed no change in flurbiprofen (CYP 2C9 substrate) in vivoLycium barbarumcase report of increased INRDanshen - case reports of increased INR with warfarinDong quai - case reports of increased INR with warfarinAmerican Ginseng - decreased INR with warfarin (Panax quinquifolius)Green tea -case report of decreased INR with warfarin but huge amountCoQ10 - case reports of decreased INR with warfarin but human study showed no effect on INRGlucosamine-increased INR cases with warfarinChondroitin-increased INR cases with warfarin

From: Lam AY, Mohutsky MA and Elmer GW. Probable herbal/drug interaction between warfarin and a common Chinese herb, Lycium barbarum. Ann Pharmacother 2001;35:1199-1201

Chart1

2.1

2.8

2.9

2.8

2

1.7

2.5

4.1

2.4

2

2.2

2.5

2.5

2.1

2

Date

INR value

Fig. 1 Patient INR Values

8/18

7/27

4/5

2/16

11/10

10/8

11/7

8/29

9/7

8/7

8/2

6/30

5/26

12/15/99

1/12/00

Sheet2

11/10/9912/15/991/12/002/16/004/5/005/26/006/30/007/27/008/2/008/7/008/18/008/29/009/7/0010/8/0011/7/00

2.12.82.92.821.72.54.12.422.22.52.52.12

Sheet2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

INR

INR values (7/99-11/00)

Sheet3

Table 4a Significant Risk of CAM-drug Adverse Interaction n=5052 (16,173 interviews)Potential EventMechanismaNumberb OccurrencescRisk of bleedsAspirinno. patientsall occurrencesGarlic23;25-27PD147 214Ginkgo24;28PD102127WarfarinGarlic25-27PD13 16Ginkgo29PD7 7Ginseng32;33PKd3 3TiclopidineGarlic23;25-27PD46Ginkgo24;30;31;54PD2 3PentoxifyllineGinkgo24;30;31PD3 3Total281 (5.6%)380 Elmer et al. Ann Pharmacother 2007;41:1617-1624

Elmer et al. Ann Pharmacother 2007;41:1617-1624

Table 4b

Significant Risk of CAM-drug Adverse Interaction

Potential EventMechanismaNumberb Occurrencesc

Decreased drug benefit

Digoxin

St. Johns wort21;34PKe2

2

Felodipine

St. Johns wort21;52PKf2

2

Tamoxifen

Garlic41

PKf4

5

Other

Furosemide/Aloe55

PD3

3

Thyroid/Kelp56

PD2

2

Grand Total

294

393

Garlic interactions:

168

241

Ginkgo interactions:

114

140

Garlic plus ginkgo:

282 (96%) 381 (97%)

Seem to have low pharmacokinetic drug interaction potential based on recent studiesGingerValerianMilk thistleSaw palmettoBlack cohoshCoQ10glucosamine

Glucosamine and type 2 diabeticsstudy examined the effect of 90d of Cosamin DS or placebo on glycosylated hemoglobin levels in type 2 diabetics. N=38 result: no effectArch Intern Med 2003;163:1587-90

Knudsen J, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy 2008;28:540-8.

several cases plus 20 reports from FDA MedWatch database. Increased INR on warfarin plus glucosamine or glucosamine/chondroitin

Herbals affecting drug management (i.e., herbal/drug interactions)literature analysis (Fugh-Berman and Ernst, Herbal Drug Interactions and Assessment of Reliability Br J Clin Pharmacol 2001;52:587-595) 108 reported cases of suspected interactions 69% unable to be evaluated 19% possible interactions 13% (14) well documented 11/14 involved warfarin 7/14 involved St. Johns wort

Top 20 Selling Herbals for 2007- Mass Market HerbalGram 2008;78:61-62ProductPossible interaction1. soy may block action of tamoxifen2. cranberry 3. garlic product dependent Inhibition of 3A4; enhance warfarin effect 4. ginkgo may increase bleed risk; may induce 2C19 5. saw palmetto6. echinacea may inhibit CYP 1A2 7. black cohosh weak 2D6 induction action (?)8. milk thistle9. ginseng Panax quiquifolius may induce 2C910. St. Johns wort definitive interactions; induce 3A4, other CYP and Pgp11. Green tea 12. Evening primrose oil may enhance warfarin effect13. valerian14. Horny goat weed enhance warfarin effect and increase BPRed indicates risk for drug interactions

Top 20 Selling Herbals for 2007- Mass Market HerbalGram 2008;78:61-62Productpossible interaction15. bilberry16. grape seed17. Yohimbe affect BP medications18. red clover19. Horse chestnut seed20. ginger

Red indicates potential risk for drug interactionsNote: total herbal sales are estimated at $4.7 billionThe above figures include only sales from food stores, drug stores, and mass market retailers but with Wal-Mart figures not included. It does not include warehouse buying clubs (Costco), convenience stores, natural foods stores, multilevel marketers, health professional sales, mail order or internet sales.

Gary Elmers assessment of herbal/drug interaction potential (in rank order of significance)(11/13/08)St. Johns wort induces CYP and Pgp; dont take with other drugs unless the drugs have a large therapeutic range and are not life saving drugsAmerican ginseng (Panax quinquefolius) induces CYP2C9; not with warfarin, tolbutamide and other 2C9 substratesGoldenseal induces CYP3A4 and 2D6. This herbal is not recommended due to lack of efficacy proof and potential interactionsGarlic and ginkgo dont take with antiplatelet adhesion drugs or aspirin or with warfarin (risk of bleeds); this is a pharmacodynamic effect. Risk may be over stated based on recent evidence.Ginkgo may induce CYP2C19 so may lower 2C19 substrates Echinacea may induce CYP1A2 so may lower 1A2 substrates

References with Good Herbal/Drug Interactions DiscussionTop 100 Drug Interactions Hansten PD and Horn JD. H&H Publications 2008

Natural Medicines Comprehensive Database. Online version updated daily. UW Healthlinks http://www.naturaldatabase.com/; $92

Recent ReviewsIzzo AA. Herb-drug interactions: an overview of the clinical evidence. Fundam Clin Pharmacol. 2005 Feb;19(1):1-16.Ernst E. Prescribing herbal medications appropriately. J Fam Pract. 2004 Dec;53(12):985-8. Skalli S, Zaid A, Soulaymani R. Drug interactions with herbal medicines. Ther Drug Monit. 2007 Dec;29(6):679-86Chavez ML, Jordan MA, Chavez PI. Evidence-based drug--herbal interactions.Life Sci. 2006;78:2146-57.

What can we do?dialog with NDs and other prescribers

recommend the best products

ask patients about herbals they may be taking

herbals should not usually be recommended for acute or serious illnesses

avoid herbal use with drugs with narrow therapeutic window, esp. warfarin, cyclosporin, digoxin, HIV protease inhibitors, theophylline, carbamazepine

stay informed

To investigate the potential herbal-drug interactions with warfarin To examine the effect of herbal medicines on clotting statusCommonly used herbal medicinesSt Johns wort, Asian ginsengginkgo biloba, gingercranberry juice, garlicHerb-drug interactions with warfarinJiang et al, Brit J Clin Pharmacol 2004, 2005,

To investigate the potential herbal-drug interactions with warfarin To examine the effect of herbal medicines on clotting statusCommonly used herbal medicinesSt Johns wort

cranberry juice Herb-drug interactions with warfarinJiang et al, Brit J Clin Pharmacol 2004, 2005,I will focus on these herbal medicines

St Johns WortIn vitro study: inhibit human CYP2D6, CYP3A4 and CYP2C9 Budzinski et al, Phytomedicine 2000In vivo study in healthy subjects: induce human CYP3A4, CYP2E1, CYP1A2 and P-glycoproteinCase reports: reduce the efficacy of warfarinFugh-Berman & Ernst, Br J Clin Pharmacol 2001

Comparison of German St Johns Wort Products according to hyperforin and total hypericin content

Wurglics et al, J Am Pharm Assoc 2001

Mueller et al, Clin Pharmacol Ther 2004St Johns wort dose and preparation on herb-drug interaction with digoxin

TLC of Proprietary St Johns Wort ProductsA: Hypericin; B: Pseudohypercin; C: Hyperoside; D: Rutin;No. 5: Use in the trial-A-B-D-CTLC of different commercial St Johns wort 1 2 3 4 5 6(British Pharmacopoeia 2001)

Study Designrandomised, open label, three-treatment, three-sequence, crossover design 14-day washout periodsingle 25 mg dose of warfarin with or without treatment with herbal medicinesBlood samples collected at -48, -24, 0 and up to 168 h

Mechanisms of drug interactionsPHARMACOKINETICPHARMACODYNAMICPHARMACEUTICAL

S-warfarin S-7-hydroxywarfarin

Park et al, 1998CYP2C9

Effect of St Johns wort and Asian ginseng on the Pharmacodynamics of Warfarin*P

S-warfarin PK data shownJiang et al, Br J Clin Pharmacol 2004

All herbs INR

0.950.70.79

1.160.881.01

1.050.810.93

1.150.931.01

1.53712626821.06151142681.2773711669

1.1906043330.82220968470.9894071019

90% CI-High

90% CI-Low

Mean ratio

Log transformed INRAUC ratio

AUC of INR

All herbs - AUC

0.830.650.73

0.980.820.89

1.030.890.97

1.030.890.95

1.16792983320.93539158071.0452137259

1.19103561910.9538969371.0658917529

90% CI-High

90% CI-Low

Mean ratio

Log transformed AUC ratio

S-warfarin AUC

SJW

1.050.860.95

1.461.161.29

1.240.971.1

0.950.70.79

High

Low

Close

PK and PD parameters

90% CI of log-transformed ratio

St John's wort - Warfarin interaction

Sheet1

Mean ratio and 90% confidence interval for log transformed S-warfarin pharmacokinetics and warfarin response- St. Jhon's wort and warfarin to warfarin only treatment.

HighLowClose

Cmax1.050.860.95

CL/F1.461.161.29

V/F1.240.971.1

AUC of INR0.950.70.79

Mean ratio and 90% confidence interval for log transformed S-warfarin pharmacokinetics and warfarin response- ginseng and warfarin to warfarin only treatment.

HighLowClose

AUC0.980.820.89

Cmax1.120.91.01

t1/20.990.850.92

CL/F1.221.031.12

V/F1.140.941.04

Warfarin response (INRAUC)1.160.881.01

Mean ratio and 90% confidence interval for log transformed S-warfarin pharmacokinetics and warfarin response- ginkgo and warfarin to warfarin only treatment.

HighLowClose

AUC1.030.890.97

Cmax1.090.971.04

t1/21.040.930.98

CL/F1.120.981.05

V/F1.070.991.03


Mean ratio and 90% confidence interval for log transformed S-warfarin pharmacokinetics and warfarin response- Ginger and warfarin to warfarin only treatment.

HighLowClose

AUC1.030.890.95

Cmax1.070.941.01

t1/21.040.940.99

CL/F1.130.971.05

V/F1.080.991.03


Mean ratio and 90% confidence interval for log transformed S-warfarin pharmacokinetics and warfarin response- Cranberry and warfarin to warfarin only treatment.

HighLowClose

AUC1.170.941.05

Cmax1.300.680.94

t1/21.120.790.94

CL/F1.000.800.89

V/F1.070.860.96


Mean ratio and 90% confidence interval for log transformed S-warfarin pharmacokinetics and warfarin response- Garlic and warfarin to warfarin only treatment.

HighLowClose

AUC1.190.951.07

Cmax1.470.771.06

t1/21.180.830.99

CL/F1.170.941.05

V/F1.050.840.94


Mean ratio and 90% confidence interval for log transformed S-warfarin AUC in different treatments.

90% CI-High90% CI-LowMean ratio

St John's wort0.830.650.73

Ginseng0.980.820.89

Ginkgo1.030.890.97

Ginger1.030.890.95

Cranberry1.170.941.05

Garlic1.190.951.07

Mean ratio and 90% confidence interval for log transformed INRAUC for different treatments.

90% CI-High90% CI-LowMean ratio

St John's wort0.950.700.79

Ginseng1.160.881.01

Ginkgo1.050.810.93

Ginger1.150.931.01

Cranberry1.541.061.28

Garlic1.190.820.99

Sheet1

High

Low

Close

PK and PD parameters

Log transformed ratio

Mean ratios and 90% CI of log tranformed S-warfarin PK and warfarin response- Ginseng and warfarin to warfarin only treatment

Sheet2

000

000

000

000

000

000

High

Low

Close

Parameters


Mean ratio and 90% CI of log transformed S-warfarin PK and warfarin response-Ginkgo and warfarin to warfarin only treatment

Sheet3

000

000

000

000

000

000

High

Low

Close

Parameter


Mean ratio and 90% CI of log tranformed S-warfarin PK and warfarin response- Ginger and warfarin to warfarin only treatment

000

000

000

000

000

000

High

Low

Close

Parameter

Log transformed

Mean ratio and 90% CI of log tranformed S-warfarin PK and warfarin response- Cranberry and warfarin to warfarin only treatment

000

000

000

000

000

000

High

Low

Close

Parameter


Mean ratio and 90% CI of log transformed S-warfarin PK and warfarin response-Garlic and warfarin to warfarin only treatment

Mortality and INROden and Fahlen, BMJ 2002

St Johns wort can reduce the effectiveness of many medicinesPretreatment with SJW significantly Mills E et al. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329:27-30.

St Johns wort can reduce the effectiveness of many medicinesPretreatment with SJW significantly Mills E et al. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329:27-30. Jiang X et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004

Rindone and Murphy, Warfarin-Cranberry Juice Interaction Resulting in ProfoundHypoprothrombinemia and Bleeding. Am J Ther 13, 283284 (2005)

Randomsied cross-over clinical trial12 healthy male subjects25 mg warfarin dose +/- 2 weeks treatment with cranberry juice extractMI Mohammed Abdul et al, 2006* p =0.017*33% increase in INR response

Chart1

9642

119.239

INR response (AUC of INR over 168 h)

Warfarin-cranberry interaction

Sheet1

Warfarin alone9642

Warfarin and Cranberry119.239

Sheet1

42

39

INR response (AUC of INR over 168 h)

Warfarin-cranberry interaction

Sheet2

Sheet3

MI Mohammed Abdul et al, 2006

Chart1

102.7938625128.0184416667167.0661572.08882560.18592557.353966666781.408841666746.41158.113075141.3441571.288462565.296525

144.0843166667105.6879666667158.173216666772.741058333371.04245119.475075119.260008333353.6322825168.5427916667168.2568208333146.012425103.0277166667

1= Warfarin only; 2 = Warfarin + cranberry

INR response (INR AUC over 7 days)

Effect of Cranberry Juice Extract on warfarin response

Sub 01

INR Data for different treatments

Subject no. 1

Warfarin aloneWarfarin and CranberryAUC ratioWarfarin and GarlicAUC ratio

TimeINR 1INR 2Avg INRINR adjustS.DAUCTimeINR 1INR 2Avg INRINR adjstS.DAUCWf cran/WfTimeINR 1INR 2Avg INRINR adjustAUCWf Gr/Wf

-46.101.191.201.200.01-47.251.181.161.170.01-44.921.251.141.20

-22.201.171.211.190.03-23.001.031.041.040.01-18.761.081.081.08

0.001.281.161.220.000.080.000.951.081.020.000.090.001.171.111.140

1.001.201.311.260.030.081.241.001.171.181.180.160.011.100.881.001.121.131.13-0.021.130.92

2.001.261.221.240.020.031.252.001.201.191.200.180.011.190.952.001.061.071.07-0.081.100.88

4.001.301.301.300.080.002.544.000.901.060.98-0.040.122.170.864.051.181.191.190.042.310.91

8.001.351.321.340.120.025.278.001.211.241.230.210.024.410.848.021.221.171.200.054.720.90

12.001.541.531.540.320.015.7412.001.321.381.350.340.045.150.9012.031.351.371.360.225.120.89

25.002.472.572.521.300.0726.3629.102.602.612.601.590.0133.791.2828.442.392.212.301.1630.031.14

49.162.892.982.941.720.0665.9051.973.223.203.212.200.0166.471.0151.842.772.562.671.5358.090.88

73.491.941.991.970.750.0459.6176.822.112.172.141.130.0466.471.1276.842.052.132.090.9559.441.00

97.241.371.481.430.210.0840.26102.581.641.631.630.620.0148.591.2199.441.721.641.680.5442.601.06

122.411.381.571.470.250.1436.47124.671.461.431.450.430.0233.990.93123.521.351.421.390.2536.901.01

146.191.271.231.250.030.0332.37145.671.411.411.410.400.0029.980.93145.521.361.391.380.2430.360.94

169.501.301.261.280.060.0329.49169.331.321.361.340.330.0332.531.10175.241.271.231.250.1139.011.32

306.48325.831.06310.811.01

baseline INR1.20baseline INR1.07baseline INR1.14

INRmax2.94INRmax3.21INRmax2.67

INR Tmax49.16INR Tmax51.97INR Tmax51.84

AUC Cor.(INR)102.79AUC Cor.(INR)144.08AUC Cor.(INR)111.33

AUC Uncor.(INR)306.48AUC UnCor.(INR)325.83AUC UnCor.(INR)310.81

Sub 01

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf alone, Sub 01

Sub 02

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf and Cran, Sub 01

sub 03

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf and Gr, Sub 01

Sub 04

000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Wf alone

Wf and Cran

Wf and Gr

Time in hours

INR

INR vs time, Sub 01

Sub 05


Subject no. 2



-45.801.281.301.290.01-46.251.351.301.330.04-44.751.331.361.35

-21.701.261.311.290.04-22.671.111.131.120.01-19.951.291.291.29

0.001.191.241.220.000.040.001.201.281.240.000.060.001.291.391.340

1.001.371.381.380.160.011.301.001.431.461.450.210.021.341.041.001.321.321.32-0.021.331.03

2.001.411.481.450.230.051.412.001.301.301.300.060.001.370.972.021.321.471.400.061.380.98

4.001.431.481.460.240.042.904.001.251.181.22-0.030.052.520.874.071.451.401.430.092.891.00

8.001.511.521.520.300.015.948.001.451.431.440.200.015.310.898.101.471.521.500.165.880.99

12.001.611.661.640.420.046.3012.001.211.231.22-0.020.015.320.8411.921.591.571.580.245.870.93

24.802.672.532.601.390.1027.1030.252.862.862.861.620.0037.231.3728.972.532.562.551.2135.171.30

48.803.283.293.292.070.0170.6254.412.562.432.501.260.0964.690.9252.332.482.392.441.1058.170.82

72.872.202.232.221.000.0266.1997.251.691.801.750.510.0890.821.3773.251.941.901.920.5845.550.69

97.231.781.921.850.640.1049.51121.331.491.611.550.310.0839.670.8097.811.931.991.960.6247.650.96

122.201.531.371.450.240.1141.20145.331.231.191.21-0.030.0333.120.80121.051.701.571.640.3041.771.01

146.201.531.491.510.300.0335.52170.501.471.471.470.230.0033.730.95150.251.601.511.560.2246.571.31

170.531.491.321.410.190.1235.460.00173.571.271.381.33-0.0133.580.95

343.45315.120.92325.820.95






Sub 05

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf alone Sub 02

sub 06

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Rime in hours

INR


Sub 07

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


Sub 08

000

000

000

000

000

000

000

000

000

000

000

000

000

000

00

Wf alone

Wf and Cran

Wf and Gr

Time in hours

INR


Sub 09


Subject no. 3



-44.781.021.041.030.01-37.490.981.021.000.03-44.521.171.101.14

-20.701.041.051.050.01-22.551.061.061.060.0020.071.121.091.11

0.000.991.011.000.000.010.001.031.081.060.000.040.001.041.091.070

1.141.071.071.070.070.001.181.211.101.031.070.010.051.281.091.121.020.900.96-0.111.130.96

2.051.031.031.030.030.000.962.071.021.031.03-0.030.010.900.942.071.051.111.080.020.971.01

4.041.031.031.030.030.002.054.171.051.051.05-0.010.002.181.064.141.171.141.160.092.311.13

8.001.161.131.150.150.024.318.451.141.241.190.140.074.791.118.001.231.131.180.124.511.05

12.121.231.251.240.240.014.9111.311.071.071.070.010.003.230.6612.001.421.421.420.365.201.06

31.252.762.762.761.760.0038.2634.682.552.682.621.560.0943.061.1326.832.512.552.531.4729.290.77

50.223.042.963.002.000.0654.6349.683.153.113.132.080.0343.090.7955.362.942.902.921.8677.741.42

80.722.612.552.581.580.0485.1082.602.432.492.461.410.0492.011.0877.062.602.752.681.6160.710.71

101.551.991.831.910.910.1146.76100.941.891.931.910.860.0340.070.86101.481.961.911.930.8756.261.20

120.801.691.661.680.680.0234.51127.281.541.531.540.480.0145.371.31130.301.561.381.470.4149.031.42

144.771.301.301.300.300.0035.66150.681.361.311.340.280.0433.580.94150.801.271.251.260.1927.930.78

175.471.221.211.220.220.0138.61171.851.241.201.220.170.0327.040.70175.061.221.141.180.1229.540.77

346.92336.610.97344.620.99






Sub 09

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


Sub 10

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


Sub 11

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


Sub 12


Subject no. 4



-46.031.301.311.310.01-46.541.351.281.320.05-46.871.371.271.32

-22.031.381.411.400.02-22.661.241.371.310.09-22.031.231.231.23

0.001.451.411.430.000.030.001.211.251.230.000.030.001.221.331.280

1.041.441.431.440.010.011.491.111.371.371.370.140.001.440.971.021.331.361.350.071.340.90

1.991.541.421.480.050.081.382.051.431.371.400.170.041.300.942.051.411.411.410.141.421.02

4.001.561.521.540.110.033.044.001.371.371.370.140.002.700.894.131.301.421.360.092.880.95

7.991.531.541.540.110.016.138.001.401.311.360.130.065.450.898.131.371.421.400.125.510.90

12.021.641.621.630.200.016.3812.071.451.391.420.190.045.650.8912.081.471.451.460.195.640.88

24.622.512.362.441.010.1125.6130.021.761.711.740.510.0428.321.1129.262.152.022.090.8130.451.19

48.362.482.642.561.130.1159.2953.022.362.302.331.100.0446.750.7950.651.981.921.950.6843.150.73

72.601.781.911.850.420.0953.3975.681.901.971.940.710.0548.320.9173.051.691.711.700.4340.880.77

97.041.651.591.620.190.0442.3497.601.721.741.730.500.0140.170.9597.651.691.581.640.3641.020.97

121.901.361.461.41-0.020.0737.66121.591.661.511.590.360.1139.761.06122.331.451.351.400.1337.450.99

146.051.421.461.440.010.0334.41154.761.431.401.420.190.0249.761.45145.491.401.411.410.1332.480.94

170.311.451.511.480.050.0435.42167.931.391.441.420.190.0418.640.53170.131.361.311.340.0633.760.95

306.55288.250.94275.980.90






Sub 12

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time, Wf alone

Summarry

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf and cran, Sub no.4

STATS

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


INR AVg

000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Wf alone

Wf and Cran

Wf and Gr

Time in hours

INR



Subject no.5



-44.211.141.121.130.01-41.211.131.191.160.04-44.181.211.171.19

-21.211.000.980.990.01-23.280.950.980.970.02-13.621.211.211.21

0.001.041.041.040.000.000.001.121.161.140.000.030.000.971.061.020

1.161.071.091.080.040.011.231.001.181.121.150.010.041.150.931.001.161.121.140.131.080.88

2.221.071.091.080.040.011.141.991.161.191.180.030.021.151.012.221.131.191.160.151.401.23

4.581.131.081.110.060.042.584.001.171.201.190.040.022.370.924.001.141.141.140.132.050.79

8.141.141.231.190.150.064.088.041.211.281.250.110.054.911.208.001.201.231.220.204.711.16

9.971.181.031.110.060.112.1011.061.311.321.320.180.013.871.8411.321.191.161.180.163.971.89

29.141.791.781.790.750.0127.7030.382.152.192.171.030.0333.671.2226.161.381.381.380.3718.960.68

51.461.691.701.700.660.0138.8454.291.891.761.830.690.0947.761.2350.561.641.621.630.6236.720.95

75.381.531.411.470.430.0837.8572.291.561.521.540.400.0330.290.8074.071.421.531.470.4636.470.96

99.791.361.391.380.340.0234.72103.061.321.321.320.180.0044.001.2798.991.361.301.330.3234.921.01

129.631.231.271.250.210.0339.17129.291.281.261.270.130.0133.970.87125.731.311.361.340.3235.630.91

150.631.241.201.220.180.0325.94150.891.301.361.330.190.0428.081.08148.561.191.221.210.1928.991.12

170.791.241.231.240.200.0124.75173.551.211.201.210.060.0128.721.16172.331.101.171.140.1227.811.12

240.08259.921.08232.710.97






0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Wf alone

Wf and Cran

Wf and Gr

Time in hours

INR



Subject no.6



-45.921.081.111.100.02-46.511.161.191.180.02-46.881.181.211.195

-19.321.221.141.180.06-16.881.351.371.360.01-23.541.041.091.065

0.001.071.091.0800.0101.161.261.2100.0701.011.061.0350

1.061.191.171.180.100.011.2011.271.421.350.140.111.281.071.120.991.021.005-0.031.140.95

2.001.071.121.100.020.041.0721.271.261.270.060.011.311.222.141.121.251.1850.151.121.04

4.131.091.101.100.020.012.3341.211.281.250.040.052.511.084.121.131.21.1650.132.331.00

8.021.101.191.150.060.064.368.021.361.391.380.170.025.271.218.041.031.041.0350.004.310.99

11.481.181.281.230.150.074.11121.451.561.510.300.085.731.3911.541.251.261.2550.224.010.98

27.892.052.022.040.960.0226.7925.292.392.42.401.190.0125.920.9725.541.992.052.020.9922.930.86

50.681.751.661.710.630.0642.6249.252.892.992.941.730.0763.911.5049.541.871.781.8250.7946.141.08

74.561.541.491.520.440.0438.4573.22.232.32.271.060.0562.331.6273.371.61.661.630.6041.171.07

98.531.311.321.320.240.0133.9296.371.841.921.880.670.0648.021.4298.541.371.421.3950.3638.071.12

122.321.361.401.380.300.0332.06120.951.491.481.490.280.0141.361.29121.371.371.41.3850.3531.730.99

147.321.191.251.220.140.0432.50145.641.451.641.550.340.1337.411.15145.71.31.321.310.2832.781.01

172.181.281.191.240.160.0630.52168.871.491.491.490.280.0035.251.16170.021.261.281.270.2431.371.03

249.91330.281.32257.101.03






0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

TIme in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in Hours

INR

INR Vs time Wf and Gr, Sub 06

000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Time in Hours

INR

INR Vs time Wf and Gr, Sub 06


Subject no. 1



-44.81.141.191.1650.0353553391-45.871.281.161.220.0848528137-45.711.161.191.18

-22.171.11.121.110.0141421356-17.621.661.591.6250.0494974747-20.881.091.051.07

01.11.111.10500.00707106780.001.181.191.18500.007071067801.171.131.150

1.171.211.111.160.0550.07071067811.3250251.001.261.271.2650.080.00707106781.2250.924510858311.181.131.160.0051.15250.8697949095

2.091.191.191.190.08501.0812.001.261.291.2750.090.02121320341.271.17483811292.041.161.171.170.0151.20641.1160037003

4.151.11.121.110.0050.01414213562.3694.001.261.301.280.0950.02828427122.5551.0785141414.20.980.990.99-0.1652.3220.9801604052

8.261.251.191.220.1150.04242640694.788157.981.351.441.3950.210.06363961035.323251.1117550628.121.191.141.170.0154.2140.8800893873

10.141.251.311.280.1750.04242640692.3512.001.601.651.6250.440.03535533916.07022.583063829812.371.251.381.320.1655.272.2425531915

25.71.671.931.80.6950.183847763123.962425.382.852.702.7751.590.106066017229.4361.228424531825.542.112.082.100.94522.454850.9370868527

49.862.42.292.3451.240.077781745950.071649.633.002.942.971.7850.042426406969.6581251.391170344149.622.082.052.070.91550.08641.0002955767

73.611.851.991.920.8150.098994949450.64687574.162.222.122.170.9850.070710678163.04211.244738199574.041.791.661.730.57546.27590.9136970445

97.861.611.581.5950.490.021213203442.61937598.081.891.871.880.6950.014142135648.4381.136525347997.371.491.531.510.3637.7362750.8854253494

121.471.271.331.30.1950.042426406934.175475121.881.651.691.670.4850.028284271242.2451.2361203465121.951.271.351.310.1634.65781.0141131908

146.21.231.241.2350.130.007071067831.345275145.761.641.741.690.5050.070710678140.11841.2798866815145.291.321.31.310.1630.57540.9754388819

168.21.091.21.1450.040.077781745926.18168.801.491.491.490.305036.63361.3992971734170.21.221.241.230.0831.63571.2083919022

270.914175346.0146751.2772114084267.5872250.9877195425






0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf alone

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Time in hours

INR



Subject no. 8



-38.51.131.131.10-37.331.071.141.110.05-35.651.121.021.07

-24.51.081.171.10.0601.081.041.060.03-24.191.211.131.17

01.091.131.100.0311.1551.111.1300.0301.241.021.130

1.171.081.031.1-0.050.041.2721.111.241.180.040.091.150.9111.111.141.13-0.001.130.89

2.171.111.141.10.020.021.093.911.061.181.12-0.010.082.192.012.051.181.111.150.021.191.09

4.091.11.131.10.010.022.157.971.1951.231.210.080.024.732.2041.081.071.08-0.052.161.01

8.091.321.321.30.210.004.8712.151.331.41.370.230.055.391.1181.171.11.140.014.420.91

10.171.241.471.40.250.162.7830.2422.022.010.880.0130.5310.9711.071.221.181.200.073.581.29

26.941.871.871.90.760.0027.0455.321.581.491.540.400.0644.451.6425.051.511.571.540.4119.150.71

46.771.711.781.70.630.0535.8282.351.391.371.380.250.0139.401.1047.821.571.491.530.4034.950.98

82.171.41.281.30.230.0854.56106.151.111.211.160.030.0730.230.5573.481.271.411.340.2136.820.67

106.61.271.231.30.140.0331.64124.611.381.281.330.200.0722.980.7396.311.251.181.220.0929.170.92

129.341.181.171.20.060.0127.57153.761.251.21.230.090.0437.241.35121.821.151.231.190.0630.681.11

168.771.21.211.20.100.0146.92171.1731.121.171.150.010.0420.630.44145.661.181.131.160.0227.950.60

172.391.131.221.180.0431.14

235.7095375238.9270551.0136503492222.350.94






0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR

INR vs time Wf and Gr

000

000

000

000

000

000

000

000

000

000

000

000

000

000

0

Time in hours

INR

INR vs time Wf and Gr


Subject no. 09



-46.581.141.141.140-44.731.141.231.190.06-43.951.191.141.165

-22.281.051.091.070.03-23.161.131.151.140.01-19.771.181.161.17

01.111.131.1200.0101.041.011.0300.020.001.071.081.0750

1.051.311.251.280.160.041.261.051.111.111.110.090.001.120.891.001.091.111.10.021.090.86

2.031.111.121.115-0.000.011.1721.161.161.160.140.001.080.922.031.101.091.0950.021.130.96

4.081.11.11.1-0.020.002.274.11.171.211.190.170.032.471.094.031.071.131.10.022.200.97

8.011.161.191.1750.050.024.4781.291.291.290.270.004.841.087.951.211.241.2250.154.561.02

11.081.451.441.4450.330.014.02121.611.511.560.540.075.701.4211.971.301.271.2850.215.051.25

27.132.872.822.8451.730.0434.4327.932.842.82.821.800.0334.891.0128.403.223.203.212.1436.931.07

48.163.433.273.352.230.1165.1456.023.493.263.382.350.1687.011.3449.323.283.323.32.2368.091.05

72.422.622.372.4951.380.1870.9076.352.542.562.551.530.0160.230.8573.402.872.742.8051.7373.501.04

98.321.941.761.850.730.1356.27100.872.042.072.061.030.0256.461.0097.072.572.452.511.4462.901.12

123.421.541.691.6150.500.1143.49124.181.591.591.590.570.0042.480.98121.822.152.002.0751.0056.741.30

147.921.321.221.270.150.0735.34151.421.241.231.240.210.0138.481.09146.071.771.731.750.6846.381.31

171.561.281.221.250.130.0429.79172.671.271.271.270.250.0026.620.89169.901.441.481.460.3938.251.28

348.54361.361.04396.811.14






0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Wf alone

Wf and Cran

Wf and Gr

Time in hours

INR

INR vs time Sub 09


Subject no. 1



-46.161.281.281.280-45.371.161.171.170.01-46.611.141.171.155

-19.371.081.111.100.02-18.941.071.201.140.09-23.71.210.971.09

01.081.141.110.000.040.001.081.081.080001.121.041.080

11.251.251.250.140.001.181.021.081.161.120.040.061.120.951.220.981.041.01-0.071.271.08

21.091.141.120.010.041.182.131.161.161.160.080.001.271.072.241.091.051.07-0.011.060.90

4.111.21.211.210.100.012.454.131.111.091.100.020.012.260.924.140.990.990.99-0.091.960.80

7.971.171.231.200.090.044.648.211.011.041.03-0.060.024.340.938.141.111.171.140.064.260.92

11.71.321.361.340.230.034.7411.481.251.421.330.250.123.850.8111.721.21.271.2350.164.250.90

27.272.712.692.701.590.0131.4525.482.362.442.401.320.0626.130.8324.82.382.352.3651.2923.540.75

51.633.593.473.532.420.0875.8849.803.313.453.382.300.1070.280.9349.393.243.113.1752.1068.110.90

73.712.362.32.331.220.0464.6975.802.612.592.601.520.0177.741.2073.42.792.72.7451.6771.071.10

97.351.781.661.720.610.0847.87100.132.262.092.181.100.1258.091.2196.471.991.991.990.9154.621.14

123.711.421.521.470.360.0742.04124.891.791.791.790.710.0049.091.17121.891.581.551.5650.4945.181.07

149.051.361.291.330.220.0535.41146.131.361.451.410.330.0633.930.96144.471.41.421.410.3333.590.95

171.151.321.211.270.160.0828.62171.971.221.221.220.140.0033.921.19169.91.281.221.250.1733.821.18

340.16362.011.06342.741.01






0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Time in hours

INR


000

000

000

000

000

000

000

000

000

000

000

000

000

000

000

Time in hours

INR

INR vs time, Sub 10


Subject no. 11



-39.231.411.4051.410.00-44.321.2951.311.300.01-39.151.291.321.31

01.351.391.370.03-21.891.091.091.090.00-22.511.421.191.31

1.121.371.281.3300.0601.271.191.2300.0601.261.271.270

2.011.251.111.18-0.150.101.111.091.211.271.240.010.041.351.211.151.141.061.10-0.171.361.22

4.011.351.321.340.010.022.522.111.221.241.230.000.011.260.502.021.281.311.300.031.040.41

7.951.421.421.420.090.005.434.171.391.281.340.110.082.640.4941.131.071.10-0.172.370.44

101.471.461.470.140.012.968.161.41.41.400.170.005.461.8581.281.191.24-0.034.671.58

26.192.512.512.511.190.0032.1810.071.531.211.370.140.232.650.08121.561.641.600.345.670.18

51.942.382.282.331.010.0762.3227.362.912.852.881.650.0436.740.5927.932.8452.822.831.5735.300.57

75.771.8851.881.880.560.0050.1950.852.983.153.071.840.1269.821.3949.73.253.413.332.0767.081.34

99.111.71.731.720.390.0241.9874.532.322.42.361.130.0664.231.5373.612.22.192.200.9366.051.57

128.61.481.591.540.210.0847.9299.621.912.041.980.750.0954.381.1397.72.072.022.050.7851.071.07

146.51.311.431.370.040.0826.00123.111.71.561.630.400.1042.341.63122.71.671.571.620.3645.811.76

172.511.321.261.29-0.040.0434.59146.111.511.511.510.280.0036.111.04146.71.411.471.440.1836.721.06

169.851.371.361.370.140.0134.13171.931.251.371.310.0434.69

30

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